Cyclopenta&#39;b! indole derivatives as spla inhibitors

ABSTRACT

A novel class of tricyclic compounds of the following formula (I) is disclosed together with the use of such compounds for inhibiting sPLA 2  mediated release of fatty acids for treatment of Inflammatory Diseases such as septic shock.

FIELD OF THE INVENTION

This invention relates to novel tricyclic compounds useful forInflammatory Diseases.

BACKGROUND OF THE INVENTION

The structure and physical properties of human non-pancreatic secretoryphospholipase A₂ (hereinafter called, “sPLA₂”) has been thoroughlydescribed in two articles, namely, “Cloning and Recombinant Expressionof Phospholipase A₂ Present in Rheumatoid Arthritic Synovial Fluid” bySeilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley;Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal ofBiological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338,1989; and “Structure and Properties of a Human Non-pancreaticPhospholipase A₂” by Kramer, Ruth M.; Hession, Catherine; Johansen,Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard,Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry,Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosuresof which are incorporated herein by reference.

It is believed that sPLA₂ is a rate limiting enzyme in the arachidonicacid cascade which hydrolyzes membrane phospholipids. Thus, it isimportant to develop compounds, which inhibit sPLA₂ mediated release offatty acids (e.g., arachidonic acid). Such compounds would be of valuein the general treatment of conditions induced and/or maintained byoverproduction of sPLA₂; such as sepsis or pain. There is a dearth ofeffective treatment for diseases associated with sPLA₂ mediated releaseof fatty acids, particularly sepsis.

Therefore, it is desirable to develop new compounds and treatments forsPLA₂ induced diseases.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I) or apharmaceutically acceptable salt, solvate, or enantiomers thereof,useful for the treatment or prevention of Inflammatory Diseases:

wherein;

-   -   R₁ is an amide, thioamide or hydrazone group represented by the        formulae,        wherein X is oxygen or sulfur; R_(a) and R_(a′), are        independently selected from hydrogen, (C₁-C₈)alkyl, or aryl;        R_(a″) is hydrogen, NH₂, (C₁-C₈)alkyl, aryl, (C₁-C₈)alkylaryl,        or arylalkyl; and n is 0, 1, or 2.    -   R₂, and R₃ are independently hydrogen, or a group containing 1        to 10 non-hydrogen atoms plus any required hydrogen atoms;    -   R₄ is the group (C₁-C₂₀)alkyl, (C₁-C₂₀)haloalkyl,        (C₂-C₂₀)alkenyl, (C₂-C₂₀)alkynyl, (C₁-C₁₀)alkylaryl,        (C₁-C₅)alkylcyclohexyl, (C₁-C₅)alkylcyclopentyl,        (C₁-C₅)alkylcycloheptyl, phenyl, benzyl, methylnaphthyl,        (C₁-C₅)alkylheterocyclic, carbocyclic radical, or heterocyclic        radical, or aryl;    -   R₅, R₆, and R₇ are independently selected from hydrogen and        non-interfering substituents;    -   R₈ is the group, -(La)-(acidic group) wherein -(L_(a))-, is an        acid linker having an acid linker length of 1 to 8;

The present invention provides novel tricyclic compounds of formula Ihaving potent and selective effectiveness as inhibitors of mammaliansPLA₂.

The present invention also relates to the use of novel tricycliccompounds of formula I useful in the treatment and/or prevention ofInflammatory Diseases.

The present invention also relates to the use of a novel tricycliccompound of formula I to inhibit mammalian sPLA₂ mediated release offatty acids.

The present invention provides a pharmaceutical composition containingany one of the tricyclic compounds of the invention.

The present invention also relates to the use of a formulationcomprising a compound of formula I, and a carrier or diluent for thetreatment or prevention of sepsis

The present invention relates to the use of a pharmaceutical compositioncomprising a therapeutically effective amount of sPLA₂ inhibitorcompounds of formula I and mixtures thereof for the manufacture of amedicament for the treatment of Inflammatory Diseases.

The present invention relates to a of a pharmaceutical compositioncomprising a therapeutically effective amount of sPLA2 inhibitorcompounds according to claim 1 and mixtures thereof for the manufactureof a medicament for the treatment of Inflammatory Diseases.

The present invention relates to the use of a compound of formula I forthe manufacture of a medicament for the treatment or prevention ofInflammatory Diseases comprising administering a therapeuticallyeffective amount of a tricyclic compound of formula (I), or apharmaceutically acceptable salt, solvate or prodrug thereof:

wherein;

-   -   R₁ is an amide, thioamide or hydrazone group represented by the        formulae,    -   wherein X is oxygen or sulfur; R_(a) and R_(a′) are        independently selected from hydrogen, (C₁-C₈)alkyl, or aryl;        R_(a″) is hydrogen, NH₂, (C₁-C₈)alkyl, aryl, (C₁-C₈)alkylaryl,        or arylalkyl; and n is 0, 1, or 2.    -   R₂, and R₃ are independently hydrogen, or a group containing 1        to 10 non-hydrogen atoms plus any required hydrogen atoms;    -   R₄ is the group (C₁-C₂₀)alkyl, (C₁-C₂₀)haloalkyl,        (C₂-C₂₀)alkenyl, (C₂-C₂₀)alkynyl, (C₁-C₁₀)alkylaryl,        (C₁-C₅)alkylcyclohexyl, (C₁-C₅)alkylcyclopentyl,        (C₁-C₅)alkylcycloheptyl, phenyl, benzyl, methylnaphthyl,        (C₁-C₅)alkylheterocyclic, carbocyclic radical, or heterocyclic        radical, or aryl;    -   R₅, R₆, and R₇ are independently selected from hydrogen and        non-interfering substituents;    -   R8 is the group, -(La)-(acidic group) wherein -(L_(a))-, is an        acid linker having an acid linker length of 1 to 8;

The present invention relates to the use of a compound of formula I forthe manufacture of a medicament for the treatment or prevention ofInflammatory Diseases comprising administering a therapeuticallyeffective amount of a tricyclic compound represented by the formulae(C1), (C2), or (C3):

I. Definitions:

The terms, “mammal” and “mammalian” include human and domesticatedquadrupeds.

The term, “Inflammatory Diseases” refers to diseases such asinflammatory bowel disease, sepsis, septic shock, adult respiratorydistress syndrome, pancreatitis, trauma-induced shock, asthma, bronchialasthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis,stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis,chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris,ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy,enteropathric spondylitis, prostrate cancer, Juvenile arthropathy orjuvenile ankylosing spondylitis, Reactive arthropathy, infectious orpost-infectious arthritis, gonoccocal arthritis, tuberculous arthritis,viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease,arthritis associated with “vasculitic syndromes”, polyarteritis nodosa,hypersensitivity vasculitis, Luegenec's granulomatosis, polymyalginrheumatica, joint cell arteritis, calcium crystal depositionarthropathris, pseudo gout, non-articular rheumatism, bursitis,tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome,repetitive use injury (typing), miscellaneous forms of arthritis,neuropathic joint disease (charco and joint), hemarthrosis(hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy,multicentric reticulohistiocytosis, arthritis associated with certaindiseases, surcoilosis, hemochromatosis, sickle cell disease and otherhemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia,hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat'sDisease, systemic lupus erythrematosis, or relapsing polychondritis andrelated diseases which comprises administering to a mammal in need ofsuch treatment a therapeutically effective amount of the compound offormula I in an amount sufficient to inhibit sPLA₂ mediated release offatty acid and to thereby inhibit or prevent the arachidonic acidcascade and its deleterious products.

The term, “tricyclic”, or “tricyclic nucleus” as used herein refers to anucleus (having numbered positions) with the structural formula (X):

The tricyclic compounds of the invention employ certain defining termsas follows:

The term, “alkyl” by itself or as part of another substituent means,unless otherwise defined, a straight or branched chain monovalenthydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, sec-butyl, n-pentyl, and n-hexyl.

The term, “alkenyl” employed alone or in combination with other termsmeans a straight chain or branched monovalent hydrocarbon group havingthe stated number ranges of carbon atoms, and typified by groups such asvinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.

The term, “hydrocarbyl” means an organic group containing only carbonand hydrogen.

The term, “halo” means fluoro, chloro, bromo, or iodo. The term,heterocyclic radical, refers to radicals derived from monocyclic orpolycyclic, saturated or unsaturated, substituted or unsubstitutedheterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3heteroatoms selected from the group consisting of nitrogen, oxygen orsulfur. Typical heterocyclic radicals are pyrrolyl, pyrrolodinyl,piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl,thiadiazolyl, benzo(b)thiophenyl, carbazolyl, norharmanyl,azabenzo(b)thiophenyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl,indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl,1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl,dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl,phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl,quinazolinyl, morpholino, thiomorpholino, homopiperazinyl,tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl,1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiophenyl,pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl,azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl andquinoxalinyl.

The term “(C₁-C₅)alkylcyclopentyl,” “(C₁-C₅)alkylcyclohexyl,” or“(C₁-C₅)alkylheterocyclic” represent a (C_(l)-C₅)alkyl group attachedrespectively to a cylopentyl, cyclohexyl, and heterocyclic group whereinthe entire group is attached to the tricyclic nucleus (X) at the alkylterminus. Therefore the mass of the entire group is the mass of the(C₁-C₅)alkyl group plus the cyclopentyl, cyclohexyl or heterocyclicgroup to which it is attached.

The term, “carbocyclic radical” refers to radicals derived from asaturated or unsaturated, substituted or unsubstituted 5 to 14 memberedorganic nucleus whose ring forming atoms (other than hydrogen) aresolely carbon atoms. Typical carbocyclic radicals are cycloalkyl,cycloalkenyl, phenyl, benzyl, spiro[5.5]undecanyl, naphthyl,norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl,terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, and anthracenyl,biphenyl, dibenzylyl and related dibenzylyl homologues represented bythe formula (a):

where n′ is a number from 1 to 8.

The terms, “non-interfering substituent”, or “non-interfering groups”refer to radicals suitable for substitution at positions 2, 3, 5, 6,and/or 7 of the tricyclic nucleus and on other nucleus substituents (ashereinafter described for Formula I), and radicals suitable forsubstitution on the heterocyclic radical and carbocyclic radical asdefined above. Illustrative non-interfering radicals are (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₇-C₁₂)arylalkyl, (C₇-C₁₂)alkylaryl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, phenyl, benzyl, toluyl, xylenyl,biphenyl, (C₁-C₈)alkoxy, C₂-C₈)alkenyloxy, C₂-C₈ alkynyloxy,(C₂-C₁₂)alkoxyalkyl, (C₂-C₁₂)alkoxyalkyloxy, C₂-C₁₂ alkylcarbonyl,(C₂-C₁₂)alkylcarbonylamino, (C₂-C₁₂)alkoxyamino,(C₂-C₁₂)alkoxyaminocarbonyl, (C₁-C₁₂)alkylamino, (C₁-C₆)alkylthio,(C₂-C₁₂)alkylthiocarbonyl, (C₁-₈)alkylsulfinyl, (C₁-C₈)alkylsulfonyl,(C₂-C₈)haloalkoxy, (C₂-C₈)haloalkylsulfonyl, (C₂-C₈)haloalkyl,(C₂-C₈)hydroxyalkyl, —C(O)O((C₂-C₈)alkyl), —(CH₂)_(n)-O—(C₁-C₈ alkyl),benzyloxy, phenoxy, phenylthio, —(CONHSO₂R), —CHO, amino, amidino,bromo, carbamyl, carboxyl, carbalkoxy, —(CH₂)_(n)-CO₂H, chloro, cyano,cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido,hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal,thiocarbonyl, and carbonyl; where n is from 1 to 8; and R is(C₁-C₈)alkyl.

The term “substituted group” is an organic group substituted with one ormore non-interfering substituents.

As used herein the terms “group”, “radical” or “fragment” are synonymousand are intended to indicate functional groups or fragments of moleculesattachable to a bond or other fragments of molecules. For exampleacetamide group represent the acetamide fragment or radical. Structuresof groups, radicals or fragments attached to the tricyclic nucleus havebeen drawn to show the first line as a connecting bond only. Thus, thegroup

represents the acetamide radical or group, not the propanamide radicalunless otherwise indicated.

The term, “(acidic group)” means an organic group which when attached toa tricyclic nucleus at the 8-position, through suitable linking atoms(hereinafter defined as the “acid linker”), acts as a proton donorcapable of hydrogen bonding. Illustrative of an (acidic group) are thefollowing:

The term, “amine”, includes primary, secondary and tertiary amines.

The term, “alkylene chain of 1 or 2 carbon atoms” refers to the divalentradicals, —CH₂—CH₂— and —CH₂—.

The term, “acid linker length” refers to the number of groups or atomsdirectly connecting from the tricyclic nucleus to the acidic group. Forexample, the group —OCH₂— has an acid linking length of 2.

The term, “group containing 1 to 10 non-hydrogen atoms” refers torelatively small groups which form substituents at the designatedposition of the tricyclic nucleus, said groups may contain non-hydrogenatoms alone, or non-hydrogen atoms plus hydrogen atoms as required tosatisfy the unsubstituted valence of the non-hydrogen atoms, forexample; (i) groups absent hydrogen which contain no more than 4non-hydrogen atoms such as —CF₃, —Cl, —Br, —NO₂, —CN, —SO₃; and (ii)groups having hydrogen atoms which contain less than 4 non-hydrogenatoms such as —CH₃, —C₂H₅, and —CH═CH₂.

The term “spiro[5.5]undecanyl” refers to the group represented by theformula;

II. The tricyclic Compounds of the Invention:

The present invention provides a novel class of tricyclic compoundsuseful as sPLA₂ inhibitors for the treatment and/or prophylaxis ofinflammation attendant to Inflammatory Diseases

The compounds of the invention are represented by the general formula(I) and include pharmaceutically acceptable salts, racemates,enantiomers, or solvates thereof;

wherein;

-   -   R₁ is an amide, thioamide or hydrazone group represented by the        formulae,    -   wherein X is oxygen or sulfur; R_(a) and R_(a′) are        independently selected from hydrogen, (C₁-C₈)alkyl, or aryl;        R_(a″) is hydrogen, NH₂, (C₁-C₈)alkyl, aryl, (C₁-C₈)alkylaryl,        or arylalkyl; and n is 0, 1, or 2.    -   R₂, and R₃ are independently hydrogen, or a group containing 1        to 10 non-hydrogen atoms plus any required hydrogen atoms;    -   R₄ is the group (C₁-C₂₀)alkyl, (C₁-C₂₀)haloalkyl,        (C₂-C₂₀)alkenyl, (C₂-C₂₀)alkynyl, (C₁-C₁₀)alkylaryl,        (C₁-C₅)alkylcyclohexyl, (C₁-C₅)alkylcyclopentyl,        (C₁-C₅)alkylcycloheptyl, phenyl, benzyl, methylnaphthyl,        (C₁-C₅)alkylheterocyclic, carbocyclic radical, or heterocyclic        radical, or aryl;    -   R₅, R₆, and R₇ are independently selected from hydrogen and        non-interfering substituents;    -   R₈ is the group, -(La)-(acidic group) wherein -(L_(a))-, is an        acid linker having an acid linker length of 1 to 8;        Preferred Subgroups of Compounds of Formula (I):        Preferred R₁ Substituents:

A preferred subgroup of R₁ is an amide, thioamide or hydrazone grouprepresented by the formula,

wherein X is oxygen or sulfur; R_(a) and R_(a′) are independentlyselected from hydrogen, (C₁-C₈)alkyl, or aryl; R_(a″) is hydrogen, NH₂,(C₁-C₈)alkyl, aryl, (C₁-C₈)alkylaryl, or arylalkyl; and n is 0, 1, or 2.

A more preferred subclass of compounds of formula (I) are those whereinX is oxygen.

Also more preferred is a subclass of compounds of formula I wherein R₁is an amide group represented by

Preferred R₂ Substituents:

R₂ is preferably selected from the group consisting of hydrogen,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, —O—((C₁-C₄)alkyl), —S—((C₁-C₃)alkyl),—(C₃-C₁₀)cycloalkyl, —CF₃, halo, —NO₂, —CN, —SO₃. Particularly preferredR₇ groups are selected from hydrogen, methyl, ethyl, propyl, isopropyl,cyclopropyl, —F, —CF₃, —Cl, —Br, or —O—CH₃.

Preferred R₃ Substituents:

R₃ is preferably selected from the group consisting of hydrogen,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, —O—((C₁-C₄)alkyl), —S—((C₁-C₃)alkyl),—(C₃-C₁₀)cycloalkyl, —CF₃, halo, —NO₂, —CN, —SO₃. Particularly preferredR₆ groups are selected from hydrogen, methyl, ethyl, propyl, isopropyl,cyclopropyl, —F, —CF₃, —Cl, —Br, or —O—CH₃.

Preferred R₄ Substituents:

Preferred R₄ groups are selected from the group consisting of(C₁-C₂₀)alkyl, (C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkylaryl, cyclohexylmethyl,cyclopentylmethyl, ethylcyclohexyl, ethylcyclopentyl, methylcycloheptyl,phenyl, benzyl, methylnaphthyl,and aryl radicals.

Preferred R₅, R₆, and R₇ Groups

A preferred R₅ or R₆ or R₇ group is a group independently selected fromthe group consisting of hydrogen, methyl, ethyl, propyl, —OCH₃,—OCH₂CH₃, halogen, phenyl and phenoxy.

Preferred R₈ Substituents:

A preferred subgroup of R8 is the group -(La)-(acidic group) wherein-(L_(a))-, is an acid linker having an acid linker length of 1, 2 or 3atoms;

Also preferred is a subclass of compounds of formula I wherein -(L_(a))-is an acid linker selected from the group consisting of;

A most preferred subgroup of R8 is the group, -(La)-(acidic group)wherein -(L_(a))-, is an acid linker represented by O—CH₂.

A preferred compound of the invention is a compound selected from thegroup consisting of:

-   (4-benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(cyclopropylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(cyclobutylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(cyclopentylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(cycloheptylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(4-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(1-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2,3-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2,3-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(2,6-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-[(3,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid,-   (4-benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(cyclopropylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(cyclobutylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(cyclopentylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(cycloheptylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(4-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(1-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2,3-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   2,3-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(2,6-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(3,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, methyl ester,-   (4-[(phenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, morpholinoethyl ester,-   (4-[(cyclohexyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, morpholinoethyl ester,-   (4-[(cyclopentyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, morpholinoethyl ester,-   (4-[(phenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, N,N-diethylacetamido ester,-   (4-[(cyclohexyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, N,N-diethylacetamido ester, and-   (4-[(cyclopentyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic    acid, N,N-diethylacetamido ester.

Preferred compounds of the invention are represented by the formulae(C1), (C2), or (C3):

The salts of the tricyclic compounds represented by formula (I), are anadditional aspect of the invention.

In those instances when the compound of the invention possesses acidicor basic functional groups, various salts may be formed which are morewater soluble and more physiologically suitable than the parentcompound. Representative pharmaceutically acceptable salts, include butare not limited to, the alkali and alkaline earth salts such as lithium,sodium, potassium, calcium, magnesium, aluminum and the like. Salts areconveniently prepared from the free acid by treating the acid insolution with a base or by exposing the acid to an ion exchange resin.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar.Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, hydrobromide, camsylate, carbonate,chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate,esylate, fluoride, fumarate, gluceptate, gluconate, glutamate,glycolylarsanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate,hydroiodide, isothionate, lactate, lactobionate, laurate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate,phosphate, polygalacturonate, salicylate, stearate, subacetate,succinate, tannate, tartrate, tosylate, trifluoroacetate,trifluoromethane sulfonate, and valerate.

Certain compounds of the invention may possess one or more chiralcenters, and thus, may exist in optically active forms. Likewise, whenthe compounds contain an alkenyl or alkenylene group, there exist thepossibility of cis- and trans-isomeric forms of the compounds. The R-and S-isomers and mixtures thereof, including racemic mixtures as wellas mixtures of cis- and trans-isomers, are contemplated by thisinvention. Additional asymmetric carbon atoms can be present in asubstituent group such as an alkyl group. All such isomers as well asthe mixtures thereof are intended to be included in the invention. If aparticular stereoisomer is desired, it can be prepared by methods wellknown in the art by using stereo-specific reactions with startingmaterials which contain the asymmetric centers and are already resolvedor, alternatively by methods which lead to mixtures of the stereoisomersand subsequent resolution by known methods. For example, a racemicmixture may be reacted with a single enantiomer of some other compound.This changes the racemic form into a mixture of stereoisomers anddiastereomers, because they have different melting points, differentboiling points, and different solubilities and can be separated byconventional means, such as crystallization.

Prodrugs are derivatives of the compounds of the invention which havechemically or metabolically cleavable groups and become by solvolysis orunder physiological conditions the compounds of the invention which arepharmaceutically active in vivo. Derivatives of the compounds of thisinvention have activity in both their acid and base derivative forms,but the acid derivative form often offers advantages of solubility,tissue compatibility, or delayed release in a mammalian organism (see,Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam1985). Prodrugs include acid derivatives well known to practitioners ofthe art, such as, for example, esters prepared by reaction of the parentacidic compound with a suitable alcohol, or amides prepared by reactionof the parent acid compound with a suitable amine. Simple aliphatic oraromatic esters derived from acidic groups pendent on the compounds ofthis invention are preferred prodrugs. In some cases it is desirable toprepare double ester type prodrugs such as (acyloxy) alkyl esters or((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters asprodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.

N,N-diethylglycolamido ester prodrugs may be prepared by reaction of thesodium salt of a compound of Formula (I) (in a medium such asdimethylformamide) with 2-chloro-N,N-diethylacetamide (available fromAldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).Morpholinylethyl ester prodrugs may be prepared by reaction of thesodium salt of a compound of formula (I) (in a medium such asdimethylformamide) with 4-(2-chloroethyl)morpholine hydrochloride(available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).

(III) Method of Preparing the Tricyclic Compound:

The tricyclic compounds of the present invention are prepared byfollowing a scheme such as Scheme 1 shown below:

Scheme 1 depicts a protocol for preparing tricyclic-compounds of theinvention starting from 6-chloro-m-anisidine (1) (available from AldrichChemical Co. Milwaukee U.S.A, and other fine chemical suppliers) orsubstituted analogs thereof. As shown, the starting material (1) isreductively aminated with benzaldehyde using a mixture of zinc chlorideand sodium cyanoborohydride as reducing agents to form the compound (2).One of skill in the art is aware that the reaction to prepare (2) may beaccomplished with other reducing agents including but not limited toNaBH₄, HCl/Zn, and NaCNBH₃. The choice of aldehyde or ketone to bereductively aminated with compound (1) determines the structure of thegroup R₄. For example, the use of formaldehyde in the reductiveamination steps would form the N-methyl analog of (2) and ultimately acompound of formula I wherein R₄ is methyl. Similarly, the use ofcyclohexylacetaldehyde in the reductive amination steps would form thecyclohexylmethyl analog of (2) and ultimately a compound of formula Iwherein R₄ is cyclohexylmethyl. A solution of compound (2) isdeprotonated at the nitrogen using a base to form a nucleophile to whichis added 2-carbomethoxy-5-bromocyclopentanone. When substitution isdesired at positions 2 and/or 3, an appropriately substituted analog of2-carbomethoxy-5-bromocyclopentanone is employed. The reaction of (2)with 2-carbomethoxy-5-bromocyclopentanone results in a tertiary aminesubstitution product (compound 3). 2-carbomethoxy-5-bromocyclopentanoneand analogs thereof may be prepared by a method similar to that reportedby Marx et al. J. Org. Chem. 1972, 37, 4489. Strong bases are preferredfor de-protonating the nitrogen atom of compound 2. Most preferred is abase selected from potassium(bistrimethylsilyl)amide, lithiumdiisopropyl amide, and n-butyllithium. After the initial base additionat about −60 to −10° C., the reaction is preferably performed at ambienttemperatures for about 4 to 24 hours. The product (3) is isolated byaqueous work-up and extraction from organic solvents such as, forexample, ethyl acetate. The product (3) may be used directly or furtherpurified by chromatography and/or crystallization by methods known toone of skill in the art. To prepare compound (4), compound (3) dissolvedin toluene or other suitable solvent is heated with zinc chloride atreflux temperature over a period of 10 to 60 hours, preferably about 48hours, to afford an intermediate tricyclic compound. The intermediatecompound is reduced by hydrogenation using palladium-on-carbon ascatalyst. Preferably, the hydrogenation is performed in ethanol or otherprotic solvent with triethylamine as acid scavenger. While otherreducing catalysts may be used, 10% palladium-on-carbon is preferred.The catalyst is also preferably wetted with ethanol before use.

The methyl ester at the 1-position of compound (4) is converted to theamide by reaction of compound (4) with excess ammonia solution. Othermethods for the conversion of esters to amides are known to one of skillin the art and may be found in general reference texts (see J. March,Advanced Organic Chemistry, 3^(rd) ed., Wiley Interscience Publishers,New York, N.Y., 1985).

The compound (5) is de-methylated by reaction with boron tribromide orsodium thioethoxide in a suitable solvent such as dichloromethane. About1.0 to 12.0 equivalents of boron tribromide is typically sufficient toeffect complete de-methylation. The de-methylation reaction temperatureis from about −12° C. to about 10° C. Work-up is initiated by stirringwith methyl alcohol or other suitable protic solvent. The stirring inmethyl alcohol is followed by neutralization with a base such as sodiumbicarbonate. This is followed by extraction and purification of theorganic phase by methods known to one of skill in the art. The product(6) is then dissolved in N,N-dimethylformamide followed by addition of aslight excess (about 1.05 mole equiv. based on (5)) of TRITON-B™(Aldrich Chemical Company, Milwaukie, USA), cesium carbonate or othermild base, and methyl bromoacetate. The mixture is stirred at ambienttemperature to afford compound (7) after about 1 to 6 hours of reaction.Compound (7) is isolated by aqueous wash followed by chromatography ofthe organic layer. Other 2-substituted haloacetates i.e. benzylbromoacetate may be used to prepare, for example, the benzyl analog of(7).

The free acid (8) is obtained by acidifying the saponification productof (7) or other basification reaction product, e.g. with potassium orlithium hydroxide. Most strong inorganic acids are suitable foracidification as described previously. However, the use of dilute HCl ispreferred. The free acid (8) may be extracted into an organic phase ifsoluble, and dried by common laboratory methods or dried by removingwater from the aqueous phase. Alternatively the saponification reaction(sodium hydroxide reaction with (8a)) product, itself a compound of theinvention, may be isolated.

Preparation of homologous amide derivatives of (I) may be accomplishedby methods known to one of skill in the art as shown for example for thepropanamide derivative below in Scheme 2.

Compound (4) from Scheme 1 is reduced to the alcohol (9), for example bylithium hydride reductions or by other methods known to one of skill inthe art. The resulting alcohol (9) may be converted to the halide,preferably chloride (10). The halogenation of the alcohol (9) may beaccomplished by use of a thionyl halide or other methods known to one ofskill in the art. The halide (10) may be activated by halogen-metalexchange reaction using for example, n-butyllithium. The activatedproduct of (10) is then reacted with ethylene oxide, for example, toafford the terminal alcohol compound (11). Conversion of the terminalalcohol (11) to an ester via an intermediate acid may be accomplished,for example, by oxidation of the alcohol (11) with sodium hypochloritein buffered t-butanol followed by esterification of the incipient acidto the ester (12). Methods for these conversions are known to one ofskill in the art and may also be found in general reference texts thathave been discussed previously.

The ester (12) may be converted to the corresponding amide derivative(13) or other substituted amide compound. For example, the reaction ofthe ester (12) with methylchloroaluminum amide in benzene or othersuitable solvent or solvent mixtures affords an intermediate amide (SeeLevin, J. I.; Turos, E.; Weinreb, S. M. An alternative procedure for thealuminum-mediated conversion of esters to amides. Syn.Comm., 1982, 12,989-993). The intermediate amide from (12) is then de-protected at the8-position by the use of boron tribromide as described previously toafford the amide (13). The amide (13) acetylated by reaction withmethylbromo acetate and TRITON-B™ (Aldrich Chemical Company, Milwaukee,USA) to afford compound (14). The conversion of compound (14) to theoxyacetic acid (15), salt or ester derivative is accomplished asdescribed previously for Scheme 1.

In an alternate and preferred procedure, the ester (12) may be preparedin a sequence as shown in Scheme 3 below

According to Scheme 3, the alcohol (9) may be oxidized to the aldehyde(10a). Oxidation of alcohol (9) to the aldehyde (10a) may beaccomplished for example, by the use of sodium hypochlorite in bufferedt-butanol, or the use of pyridinium sulfur trioxide complex withdiisopropyl ethylamine as base in dimethyl sulfoxide solvent (seeTetrahedron Letters, 28, 1603 (1987)). The aldehyde (10a) is thensubjected to a Horner-Emmons modification of the Wittig reaction toafford the α,β-unsaturated ester (11a). Preferably, a reagent forforming the α,β-unsaturated methyl ester (i.e.trimethylphosphonoacetate) is used to react with the aldehyde in thepresence of a base. Preferred bases for the Wittig type reactionsinclude n-butyllithium, sodium hydride and sodium ethoxide. The Eregio-isomer of α,β-unsaturated methyl ester or a preponderance of the Eregio-isomer may be obtained. A general review of Wittig and modifiedWittig reactions is provided in Chem. Rev., 89 863 (1989). However, theregio-isomerism of the modified Wittig reaction is irrelevant because ofthe subsequent reduction step. The unsaturated ester (11a) is reduced toafford compound (12), preferably by hydrogenation techniques such as useof hydrogen with Palladium-on-carbon catalysts. The saturated ester (12)is then converted to the amide (13) and ultimately to compound (15) andanalogs thereof as shown in Scheme 3, and described previously forScheme 1.

Compounds of formula (I) wherein for R₁ n is 1, may be prepared by aScheme such as Scheme 4 below:

For example, the halide (10) prepared according to Scheme 2 may becyanated using sodium cyanide or a soluble source of cyanide ion toafford the cyano compound (11b). The cyano compound (11b) may behydrolyzed to afford the amide compound (16). The amide (16) isconverted to compound (18) or analogs such as the oxyacetic acid methylester (17), or oxyacetic acid, sodium salt derivatives as discussedpreviously. A preferred procedure for the conversion of (11b) to (16) isthe use of a hydrogen peroxide/potassium carbonate mixture in dimethylsulfoxide solvent. The reaction is typically performed at ambienttemperatures and the product is worked up by acidic aqueous quenchfollowed by extraction. Other procedures for the conversion of the cyanogroup to the amide group may be found in previously disclosed generalreference texts.

To prepare compound of formula (I) wherein R₄ is a halo-substitutedgroup, i.e. R₄ is halosubstituted benzyl or (C₁-C₂₀)haloalkyl whereinthe halo group is chloro, bromo, fluoro or iodo, the process as shown inScheme 5 below may be utilized.

Scheme 5 in addition to its utility in preparing compounds of formula Ialso provides the the advantage of allowing alkylation of the tricyclicnitrogen (4-position of tricyclic nucleus) with haloaryl, haloalkylaryl,or haloalkyl groups after formation of the tricycle to avoiddehalogenation of such groups as may obtain following the procedure ofScheme 1. According to Scheme 5, the 6-chloro-m-anisidine isBOC-protected using t-butyloxycarbonyl anhydride (BOC anhydride) orother protecting group to form compound (19). Compound (19) is thensubstituted with 2-carbomethoxy-5-bromocyclopentanone at the nitrogen toform compound (20), using a base as described for Scheme 1. The product(20) is deprotected with trifluoroacetic acid in a suitable solvent toafford an intermediate compound which is then reductively cyclized usingzinc chloride in a suitable solvent e.g. toluene at reflux to formcompound (21). Compound (21) is dehalogenated using 10%palladium-on-carbon to afford compound (22) similar to the procedure ofScheme 1. The dehalogenated product (22) is then arylated or alkylatedat the tricyclic nitrogen using a suitable base (in the absence, orpresence, of a catalyst) and an appropriately halo-substitutedarylhalide or alkylhalide. Arylation of amines can be accomplished by awide variety of known methods and catalysts and are known to one ofskill in the art and may be found in general reference texts (seeMarch's Advanced Organic Chemistry, 5th ed., Wiley IntersciencePublishers, New York, N.Y., 2001, page 501-502), for example, accordingto the general procedures of Watanabe, M.; Nishiyama, M.; Yamamoto, T.;Koie, Y.; Tetrahedron Lett 2000, 41 (4), 481-483; Wolfe, J. P.;Buchwald, S. L.; J. Org. Chem. 1996, 61, 1133; Morita, S.; Kitano, K.;Matsubara, J.; Ohtani, T.; Kawano, Y.; Otsubo, K.; Uchida, M.;Tetrahedron [TETRAB] 1998, 54 (19), 4811-4818; Smith W. J., Sawyer J.S., Tetrahedron Lett 37(3), 299-302 (1996); and related references. Theresulting haloaryl or haloalkyl compound (23) is subjected to proceduressimilar to that shown in Scheme 1 (see compound 4 of Scheme 1) to affordthe desired halosubstituted compound (24).

IV. Methods of Using the Compounds of the Invention:

The tricyclic compounds described herein are believed to achieve theirbeneficial therapeutic action principally by direct inhibition ofmammalian (including human) sPLA₂, and not by acting as antagonists forarachidonic acid, nor other active agents below arachidonic acid in thearachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, andetc.

The method of the invention for inhibiting sPLA₂ mediated release offatty acids comprises contacting mammalian sPLA₂ with a therapeuticallyeffective amount of tricyclic compounds of Formulae (I) as describedherein including a salt or a prodrug derivative thereof.

Another aspect of this invention relates to a method for treatingInflammatory Diseases such as inflammatory bowel disease, septic shock,adult respiratory distress syndrome, pancreatitis, trauma, asthma,bronchial asthma, allergic rhinitis, rheumatoid arthritis,osteoarthritis, and related diseases which comprises administering to amammal (including a human) a therapeutically effective dose of atricyclic compound of the invention.

As previously noted the compounds of this invention are useful forinhibiting sPLA₂ mediated release of fatty acids such as arachidonicacid. By the term, “inhibiting” is meant the prevention ortherapeutically significant reduction in release of sPLA₂ initiatedfatty acids by the compounds of the invention. By “pharmaceuticallyacceptable” it is meant the carrier, diluent or excipient must becompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The specific dose of a compound administered according to this inventionto obtain therapeutic or prophylactic effect will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the route ofadministration and the condition being treated. Typical daily doses willcontain a non-toxic dosage level of from about 0.01 mg/kg to about 50mg/kg of body weight of an active compound of this invention.

Preferably compounds of the invention per Formula (I) or pharmaceuticalformulations containing these compounds are in unit dosage form foradministration to a mammal. The unit dosage form can be a capsule ortablet itself, or the appropriate number of any of these. The quantityof Active ingredient in a unit dose of composition may be varied oradjusted from about 0.1 to about 1000 milligrams or more according tothe particular treatment involved. It may be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration.

The compound can be administered by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,and intranasal.

Pharmaceutical formulations of the invention are prepared by combining(e.g., mixing) a therapeutically effective amount of the tricycliccompound of the invention together with a pharmaceutically acceptablecarrier or diluent therefor. The present pharmaceutical formulations areprepared by known procedures using well-known and readily availableingredients.

In making the compositions of the present invention, the Activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, or can be in the form of tablets, pills, powders, lozenges,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), or ointment, containing, for example, up to 10%by weight of the active compound. The compounds of the present inventionare preferably formulated prior to administration.

For the pharmaceutical formulations any suitable carrier known in theart can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. For example, for intravenousinjection the compounds of the invention may be dissolved in at aconcentration of 2 mg/ml in a 4% dextrose/0.5% Na citrate aqueoussolution. Solid form formulations include powders, tablets and capsules.A solid carrier can be one or more substance, which may also act asflavoring agents, lubricants, solubilizers, suspending agents, binders,tablet disintegrating agents and encapsulating material.

Tablets for oral administration may contain suitable excipients such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or acacia, andlubricating agents such as magnesium stearate, stearic acid, or talc. Apreferred tablet formulation for oral administration is one that affordsrapid dissolution in the mouth of a patient in need thereof.

In powders the carrier is a finely divided solid which is in admixturewith the finely divided Active ingredient. In tablets the Activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from about 1 toabout 99 weight percent of the Active ingredient which is the novelcompound of this invention. Suitable solid carriers are magnesiumcarbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, and cocoa butter.

Sterile liquid form formulations include suspensions, emulsions, syrupsand elixirs.

The Active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent or a mixture of both. The Active ingredient can often bedissolved in a suitable organic solvent, for instance aqueous propyleneglycol. Other compositions can be made by dispersing the finely dividedActive ingredient in aqueous starch or sodium carboxymethyl cellulosesolution or in a suitable oil.

The following pharmaceutical formulations 1 through 8 are illustrativeonly and are not intended to limit the scope of the invention in anyway. “Active ingredient”, refers to a compound according to Formula (I)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:Quantity (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesiumstearate  10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below: Quantity (mg/tablet)Active ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide,fumed  10 Stearic acid  5 Total 665 mg

The components are blended and compressed to form tablets each weighing665 mg

Formulation 3

An aerosol solution is prepared containing the following components:Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22(Chlorodifluoromethane) 74.00 Total 100.00

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of Active ingredient, are made asfollows: Active ingredient   60 mg Starch   45 mg Microcrystallinecellulose   35 mg Polyvinylpyrrolidone (as 10% solution in water)   4 mgSodium carboxymethyl starch  4.5 mg Magnesium stearate  0.5 mg Talc   1mg Total  150 mg

The Active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of Active ingredient, are made asfollows: Active ingredient  80 mg Starch  59 mg Microcrystallinecellulose  59 mg Magnesium stearate  2 mg Total 200 mg

The Active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 6

Suppositories, each containing 225 mg of Active ingredient, are made asfollows: Active ingredient   225 mg Saturated fatty acid glycerides2,000 mg Total 2,225 mg

The Active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of Active ingredient per 5 mL dose,are made as follows: Active ingredient   50 mg Sodium carboxymethylcellulose   50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavorq.v. Color q.v. Purified water to total   5 ml

The Active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 8

An intravenous formulation may be prepared as follows: Active ingredient  100 mg Isotonic saline 1,000 ml

The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 ml per minute.

Assay

The following chromogenic assay procedure was used to identify andevaluate inhibitors of recombinant human secreted phospholipase A₂. Theassay described herein has been adapted for high volume screening using96 well microtiter plates. A general description of this assay method isfound in the article, “Analysis of Human Synovial Fluid Phospholipase A₂on Short Chain Phosphatidylcholine-Mixed Micelles: Development of aSpectrophotometric Assay Suitable for a Microtiterplate Reader”, byLaure J. Reynolds, Lori L. Hughes, and Edward A Dennis, AnalyticalBiochemistry, 204, pp. 190-197, 1992 (the disclosure of which isincorporated herein by reference):

Reagents:

Reaction Buffer

CaCl₂.2H₂O (1.47 g/L)

KCl (7.455 g/L)

Bovine Serum Albumin (fatty acid free) (1 g/L)

-   -   (Sigma A-7030, product of Sigma Chemical Co., St. Louis Mo.,        USA)

TRIS HCl (3.94 g/L)

pH 7.5 (adjust with NaOH)

Enzyme Buffer

0.05 NaOAc.3H₂O, pH 4.5

0.2 NaCl

Adjust pH to 4.5 with acetic acid DTNB-5,5′-dithiobis-2-nitrobenzoicacid Racemic Diheptanoyl Thio-PC

racemic1,2-bis(heptanoylthio)-1,2-dideoxy-sn-glycero-3-phosphorylcholine

TRITON X-100™ prepare at 6.249 mg/ml in reaction buffer to equal 10 uM.

Reaction Mixture

A measured volume of racemic dipheptanoyl thio PC supplied in chloroformat a concentration of 100 mg/ml is taken to dryness and redissolved in10 millimolar TRITON X-100™ nonionic detergent aqueous solution.Reaction Buffer is added to the solution, then DTNB to give the ReactionMixture.

The reaction mixture thus obtained contains 1 mM diheptanoly thio-PCsubstrate, 0.29 mm Triton X-₁₀₀™ detergent, and 0.12 mm DTMB in abuffered aqueous solution at pH 7.5.

Assay Procedure:

1. Add 0.2 ml reaction mixture to all wells;

2. Add 10 ul test compound (or solvent blank) to appropriate wells, mix20 seconds;

3. Add 50 nanograms of sPLA₂ (10 microliters) to appropriate wells;

4. Incubate plate at 40° C. for 30 minutes;

5. Read absorbance of wells at 405 nanometers with an automatic platereader.

Tests were done in triplicate. Typically, compounds were tested at afinal concentration of 5 ug/ml. Compounds were considered active whenthey exhibited 40% inhibition or greater compared to uninhibited controlreactions when measured at 405 nanometers. Lack of color development at405 nanometers evidenced inhibition. Compounds initially found to beactive were re-assayed to confirm their activity and, if sufficientlyactive, IC₅₀ values were determined. Typically, the IC₅₀ values (see,Table I, below) were determined by diluting test compound seriallytwo-fold such that the final concentration in the reaction ranged from45 ug/mL to 0.35 ug/ml. More potent inhibitors required significantlygreater dilution. In all cases, % inhibition measured at 405 nanometersgenerated by enzyme reactions containing inhibitors relative to theuninhibited control reactions was determined. Each sample was titratedin triplicate and result values were averaged for plotting andcalculation of IC₅₀ values. IC₅₀ values were determined by plotting logconcentration versus inhibition values in the range from 10-90%inhibition. Results Compound of Example# IC₅₀ (μM) (micromolar) 1 0.046

While the present invention has been illustrated above by certainspecific embodiments, it is not intended that these specific examplesshould limit the scope of the invention as described in the appendedclaims.

Experimental

All of the products of the Examples described below as well asintermediates used in the following procedures showed satisfactory NMRand IR spectra. They also had the correct mass spectral values.

EXAMPLE 1

Part A.

N-benzyl-2-chloro-5-methoxyaniline

A solution of 6-chloro-m-anisidine (9.80 g; 62.2 mmol), benzaldehyde(7.60 mL; 74.62 mmol) and ZnCl₂ (10.20 g; 74.62 mmol) in 200 mL of MeOHwas treated NaCNBH₃ (4.70 g; 74.62 mmol) in 0.5 g portions. The reactionwas heated to reflux for about 2 hours, allowed to cool and additionalNaCNBH₃ (1.95 g; 31.03 mmol) added. The mixture was stirred at ambienttemperature for 72 hrs, poured into aqueous 1 N NaOH (400 mL), andextracted multiple times with Et₂O (1 L total). The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Theblack solid was purified by MPLC (1.25% EtOAc in hexanes) to afford thetitle compound as an oil (8.46 g; 32.89 mmol; 55%). ¹H NMR (CDCl₃) 67.44-7.27 (m, 5H), 7.20-7.14 (m, 1H), 6.26-6.18 (m, 2H), 4.72 (br s,1H), 4.38 (d, J=5.6 Hz, 2H), 3.71 (s, 3H); IR (CHCl₃) 1604, 1583, 1513,1466, 1453, 1318, 1173, 1027 cm⁻¹; FDMS 248 (M+1); Anal. calcd forC₁₄H₁₄NOCl: C, 67.88; H, 5.70; N, 5.65. Found: C, 68.05; H, 5.64; N,5.72.

Part B.

A 0° C. solution of N-benzyl-2-chloro-5-methoxyaniline (3.00 g; 12.11mmol) from part A, in 75 mL THF was treated with potassiumbis(trimethylsilyl)amide (0.5 M in toluene; 50.0 mL; 25.0 mmol) in adropwise manner. After stirring 15 min at 0° C., a solution of2-carbomethoxy-5-bromocyclopentanone (Marx et al. J. Org. Chem. (1972),37, 4489: 2.94 g; 13.32 mmol) in 5 mL THF was added dropwise. Thereaction was stirred at ambient temperature for 16 hrs and was quenchedwith brine (200 mL). The two layers were separated and the aqueous phaseextracted with EtOAc. The combined organic layers were dried (Na₂SO₄),filtered, and concentrated in vacuo to give 4.46 g of an oil.Purification by chromatography (5% EtOAc in hexanes) afforded 2.10 g(5.41 mmol; 45%) of3-[Benzyl-(2-chloro-5-methoxy-phenyl)-amino]-2-hydroxy-cyclopent-1-enecarboxylicacid methyl ester, compound 3, Scheme 1, as an oil. IR (CHCl₃) 1757,1728, 1592, 1480, 1465, 1446, 1241, 1199, 1173 cm⁻¹; FDMS 388 (M+1);Anal. calcd for C₂₁H₂₂NO₄Cl.0.4 H₂O: C, 63.84; H, 5.43; N, 3.94. Found:C, 63.51; H, 5.64; N, 5.72.

Part C.

A mixture of(3-[Benzyl-(2-chloro-5-methoxy-phenyl)-amino]-2-hydroxy-cyclopent-1-enecarboxylicacid methyl ester) (9.30 g; 24.00 mmol) and solid ZnCl₂ (13.20 g; 97.00mmol) in 200 mL toluene was heated to reflux for 48 hrs. The mixture wascooled, concentrated in vacuo, and the oil purified by chromatography(5% EtOAc in hexanes) to afford 0.50 g (1.35 mmol; 5.6%) of cyclizedproduct which was taken on to the next step without furtherpurification.

A solution of the above cyclized product (0.75 g; 2.03 mmol) and TEA(1.0 mL) in EtOH (40 mL) was treated with 10% Pd-C (100 mg) which hadbeen pre-wetted with EtOH. The mixture was hydrogenated at atmosphericpressure for 16 hrs. The catalyst was filtered and the mother liquorconcentrated in vacuo. The oil was purified by radial chromatography(10% then 15% EtOAc in hexanes) to afford 0.34 g (1.00 mmol; 50%) of4-Benzyl-8-methoxy-1,2,3,4-tetrahydro-cyclopenta[b]indole-1-carboxylicacid methyl ester, compound 4, Scheme 1, as an oil. ¹H NMR (CDCl₃) δ7.29-7.18 (m, 3H), 7.07 (d, J=8.7 Hz, 2H), 6.98 (app t, J=8.7 Hz, 1H),6.80 (d, J=8.3 Hz, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.19 (d, J=7.4 Hz, 2H),4.20-4.14 (m, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 2.96-2.60 (m, 4H); IR(CHCl₃) 3008, 1729, 1563, 1496, 1449, 1435, 1259, 1172, 1109 cm⁻¹; HRMScalcd for C₂₁H₂₁NO₃: 335.1521. Found: 335.1526.

Part D.

A slurry of NH₄Cl (174 mg; 3.25 mmol) in toluene (7 mL) at about 0° C.was slowly treated with trimethylaluminum (2N in toluene: 1.60 mL; 3.20mmol). The cold bath was removed and the mixture stirred for 1 hr atambient temperature (gas evolution ceased). A solution of4-Benzyl-8-methoxy-1,2,3,4-tetrahydro-cyclopenta[b]indole-1-carboxylicacid methyl ester, (310 mg; 0.92 mmol) in 6 mL toluene: CH₂Cl₂ (5:1) wasadded dropwise and the reaction heated to 50° C. for 18 hrs. The mixturewas allowed to cool, quenched with 0.1 N aqueous HCl (10 mL) andextracted with CH₂Cl₂ (4×20 mL). The combined organic layers were washedwith H₂O (50 mL) and concentrated in vacuo to afford a solid.Purification by radial chromatography (30% EtOAc in hexanes) afforded158 mg (54%) of4-Benzyl-8-methoxy-1,2,3,4-tetrahydro-cyclopenta[b]indole-1-carboxylicacid amide (compound 5, Scheme 1) as a white solid. ¹H NMR (CDCl₃) δ7.28-7.21 (m, 3H), 7.09-7.00 (m, 4H), 6.87 (d, J=8.3 Hz, 1H), 6.55 (d,J=7.8 Hz, 1H), 5.19 (s, 2H), 4.12-4.07 (m, 1H), 3.95 (s, 3H), 3.12-3.04(m, 1H), 2.99-2.92 (m, 1H), 2.73-2.61 (m, 2H); IR (CHCl₃) 3403, 3163,1676, 1496, 1447, 1433, 1352, 1255, 1099, 775, 736, 699 cm⁻¹; HRMS calcdfor C₂₀H₂₁N₂O₂: 321.1603. Found: 321.1607.

Part E.

A −20° C. slurry of4-Benzyl-8-methoxy-1,2,3,4-tetrahydro-cyclopenta[b]indole-1-carboxylicacid amide (150 mg; 0.47 mmol) in CH₂Cl₂ (5 mL) was treated with BBr₃ (1M in CH₂Cl₂: 4.70 mL; 4.70 mmol). The cold bath was removed and thereaction was stirred at ambient temperature for about 3 hours. Thereaction was poured onto ice and the mixture extracted with CH₂Cl₂ (4×10mL). The combined organic layers were washed with H₂O, dried (Na₂SO₄),filtered and concentrated in vacuo to give a foam.

Purification by radial chromatography (40% EtOAc in hexanes) afforded 81mg (0.26 mmol; 56%)4-Benzyl-8-hydroxy-1,2,3,4-tetrahydro-cyclopenta[b]indole-1-carboxylicacid amide, compound 6, Scheme 1. ¹H NMR (DMSO-d₆) δ 10.50 (br s, 1H),7.60 (br s, 1H), 7.34 (br s, 1H), 7.30-7.18 (m, 3H), 7.10 (d, J=7.3 Hz,2H), 6.82-6.76 (m, 2H), 6.32 (dd, J=5.4 and 3.0 Hz, 1H), 5.20 (s, 2H),3.99 (t, J=5.8 Hz, 1H), 2.87-2.79 (m, 1H), 2.73-2.60 (m, 3H); IR (KBr)3347, 3190, 1656, 1594, 1562, 1496, 1452, 1352, 1250, 730 cm⁻¹; HRMScalcd for C₁₉H₁₉N₂O₂: 307.1447. Found: 307.1449.

Part F.

A solution4-Benzyl-8-hydroxy-1,2,3,4-tetrahydro-cyclopenta[b]indole-1-carboxylicacid amide (75 mg; 0.24 mmol) in DMF (3 mL) at about 0° C. was treatedwith Triton-B (40% w/v in MeOH: 0.13 mL; 0.31 mmol) and the mixturestirred for 15 min. Methyl bromoacetate (0.07 mL; 0.74 mmol) was addeddropwise. The reaction stirred at 0° C. for 1 hr, poured into 1 Naqueous HCl (10 mL), and the mixture diluted with EtOAc (10 mL). The twolayers were separated and the aqueous phase extracted with EtOAc (4×40mL). The combined organic layers were washed with 1 N aqueous HCl (10mL), H₂O (10 mL), brine (10 mL), dried (Na₂SO₄), filtered, andconcentrated in vacuo to give 103 mg of a solid. Purification by radialchromatography (10% then 15% then 25% then 40% EtOAc in hexanes)afforded 51 mg (56%) of(4-Benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid methyl ester compound 7, Scheme 1, as a white solid.

¹H NMR (CDCl₃) δ 7.36 (br s, 1H), 7.23-7.14 (m, 4H), 6.99 (d, J=8.6 Hz,2H), 6.90 (app t, J=7.9 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.35 (d, J=7.3Hz, 1H), 5.12 (s, 2H), 4.68 (AB q; J=15.6 and 50.1 Hz, 2H), 4.11-4.05(m, 1H), 3.77 (s, 3H), 3.04-2.97 (m, 2H), 2.62-2.54 (m, 2H); IR (KBr)3409, 1752, 1677, 1438, 1239, 1225, 1117, 734 cm⁻¹; FDMS, 379 (M+1);Anal calcd for C₂₂H₂₂N₂O₄.1.0 H₂O: C, 66.65; H, 6.10; N, 7.07. Found: C,66.80; H,5.80; N, 6.93.

Part G

A slurry of(4-Benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid methyl ester (24 mg; 0.06 mmol) in THF (2 mL) and MeOH (0.7 mL) wastreated with 1N aqueous LiOH (0.1 mL). The mixture was stirred for 14hrs and was concentrated in vacuo. Purification by reverse phasechromatography (Vydac C₁₈column; 5% to 70% of 0.1% HCl/H₂O in 0.1%HCl/CH₃CN) afforded 21 mg (92%)(4-Benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, compound 8, Scheme 1, as a white solid. ¹H NMR (CDCl₃) δ 7.30-7.19(m, 4H), 7.09 (d, J=7.3 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 6.87 (app t,J=7.8 Hz, 1H), 6.67 (br s, 1H), 6.42 (d, J=7.8 Hz, 1H), 5.25 (s, 2H),4.66-4.51 (m, 2H), 3.85 (d, 7.8 Hz, 1H), 2.96-2.84 (m, 1H), 2.76-2.62(m, 3H); IR (KBr) 3413, 1716, 1667, 1636, 1614, 1496, 1432, 1256, 1115,721, 701 cm⁻¹; FDMS, 365 (M+1); Anal calcd for C₂₁H₂₀N₂O₄.0.5 HCl: C,64.92; H, 5.40; N, 7.32. Found: C, 64.75; H,5.65; N, 7.13.

1. A tricyclic compound represented by the formula (I), or apharmaceutically acceptable salt, or solvate thereof;

wherein; R₁ is an amide, thioamide or hydrazone group represented by theformulae,

wherein X is oxygen or sulfur; R_(a) and R_(a′) are independentlyselected from hydrogen, (C₁-C₈)alkyl, or aryl; R_(a″) is hydrogen, NH₂,(C₁-C₈)alkyl, aryl, (C₁-C₈)alkylaryl, or arylalkyl; and n is 0, 1, or 2.R₂, and R₃ are independently selected from the group consisting ofhydrogen, (C₁ -C₄)alkyl, (C₂-C₄)alkenyl, —O—(C₁-C₃ alkyl), —S—(C₁-C₃alkyl), (C₃-C₄)cycloalkyl, —CF₃, halo, —NO₂, —CN, or —SO₃; R₄ is thegroup (C₁-C₂₀)alkyl, (C₁-C₂₀)haloalkyl, (C₂-C₂₀)alkenyl,(C₂-C₂₀)alkynyl, (C₁-C₁₀)alkylaryl, (C₁ -C₅)alkylcyclohexyl,(C₁-C₅)alkylcyclopentyl, (C₁-C₅)alkylcycloheptyl, phenyl, benzyl,methylnaphthyl, (C₁-C₅)alkylheterocyclic, carbocyclic radical, orheterocyclic radical, or aryl; R₅, R₆, and R₇ are independently selectedfrom hydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl,(C₇-C₁₂)arylalkyl, (C₇-C₁₂)alkylaryl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkenyl, phenyl, toluyl, xylenyl, benzyl, biphenyl,(C₁-C₈)alkoxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy,(C₂-C₁₂)alkoxyalkyl, (C₂-C₁₂)alkoxyalkyloxy, (C₂-C₁₂)alkylcarbonyl,(C₂-C₁₂)alkylcarbonylamino, (C₂-C₁₂)alkoxyamino,(C₂-C₁₂)alkoxyaminocarbonyl, (C₁-C₁₂)alkylamino, (C₁-C₆)alkylthio,(C₂-C₁₂)alkylthiocarbonyl, (C₁-C₈)alkylsulfinyl, (C₁-C₈)alkylsulfonyl,(C₂-C₈)haloalkoxy, (C₁-C₈)haloalkylsulfonyl, (C₂-C₈)haloalkyl,C₁-C₈)hydroxyalkyl, —C(O)O(C₁-C₈ alkyl), —(CH₂)_(n)-O—(C₁-C₈)alkyl),benzyloxy, phenoxy, phenylthio, —(CONHSO₂R), —CHO, amino, amidino,bromo, carbamyl, carboxyl, carbalkoxy, —(CH₂)_(n)-CO₂H, chloro, cyano,cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido,hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal,thiocarbonyl, and carbonyl; where n is from 1 to 8, and R is(C₁-C₄)alkyl, phenyl or (C₇-C₁₂)aryl.; R₈ is the group, -(La)-(acidicgroup) wherein -(L_(a))-, is an acid linker having an acid linker lengthof 1 to 8;
 2. The compound of claim 1 wherein R₂ and R₃ are eachindependently selected from hydrogen, (C₁-C₄)alkyl, (C₂-C₄)alkenyl,—O—(C₁ -C₃ alkyl), —S—(C₁-C₃ alkyl), (C₃-C₄)cycloalkyl, and —CF₃.
 3. Thecompound of claim 1 wherein R₈ is the group, -(La)-(acidic group) andwherein the (acidic group) is selected from the group: —COOH-5-tetrazolyl, —SO₃H,


4. The compound of claim 1 wherein R₁ is the group represented by theformula;


5. The compound of claim 1 wherein R₁ is the group


6. The compound of claim 1 wherein R₁ is the group


7. The compound of claim 1 wherein, for R₅ or R6 or R₇, thenon-interfering substituent is independently selected from hydrogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl, (C₇-C₁₂)arylalkyl,(C₇-C₁₂)alkylaryl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, phenyl,toluyl, xylenyl, benzyl, biphenyl, and (C₁-C₈)alkoxy.
 8. The compound ofclaim 1 wherein R₈ is the group, -(La)-(acidic group) and wherein the(acidic group) is selected from the group consisting of —COOH, —COONa,and —COOK.
 9. The compound of claim 1 wherein the prodrug is the methylor ethyl or N-methylmorpholino ester of a compound of formula (I).
 10. Acompound selected from the group consisting of:(4-benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(cyclopropylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(cyclobutylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(cyclopentylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(cycloheptylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, (4-[(3-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(4-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(1-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2,3-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2,3-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(2,6-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-[(3,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid,(4-benzyl-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-phenoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-fluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-chlorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-bromophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-iodophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-acetamidophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-carbamoylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-methylsulfonylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-methylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-ethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-trifluoromethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(cyclopropylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(cyclobutylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(cyclopentylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(cycloheptylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-methoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-ethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-trifluoromethoxyphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-cyanophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-pyridyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-furyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-thienyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-benzyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(4-phenylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(1-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2-napthyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2,3-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-acetic acid, methyl ester,(4-[(3,4-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3,5-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3,6-difluorophenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,2,3-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(2,6-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3,4-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(3,5-dimethylphenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, methyl ester,(4-[(phenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, morpholinoethyl ester,(4-[(cyclohexyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, morpholinoethyl ester,(4-[(cyclopentyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, morpholinoethyl ester,(4-[(phenyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, N,N-diethylacetamido ester,(4-[(cyclohexyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, N,N-diethylacetamido ester, and(4-[(cyclopentyl)methyl]-1-carbamoyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-8-yloxy)-aceticacid, N,N-diethylacetamido ester.
 11. A tricyclic compound representedby the formulae (C1), (C2), or (C3):


12. A pharmaceutical formulation comprising a tricyclic compound offormula (I) together with a pharmaceutically acceptable carrier ordiluent.
 13. A method of inhibiting sPLA₂ mediated release of fatty acidcomprising contacting sPLA₂ with a therapeutically effective amount oftricyclic compound of formula (I).
 14. A method of treating a mammal,including a human, to alleviate the pathological effects of InflammatoryDiseases wherein the method comprises administering to said mammal atherapeutically effective amount of a compound of formula (I).
 15. Apharmaceutical formulation comprising a therapeutically effective amountof the compound of formula (I) useful for the treatment and/oramelioration of Inflammatory Diseases.
 16. A pharmaceutical formulationcomprising a therapeutically effective amount of the compound of formula(I) useful for inhibiting sPLA₂ mediated release of fatty acid.
 17. Useof a pharmaceutical composition comprising a therapeutically effectiveamount of sPLA₂ inhibitor compounds according to formula (I) andmixtures thereof for the manufacture of a medicament for the treatmentof Inflammatory Diseases.
 18. (Canceled)
 19. (Canceled)